There are currently ˜2.5 million breast cancer survivors in the United States. Breast cancer affects ˜180,000 new Americans annually, and kills 40,000 patients (Ries, “SEER Cancer Statistics Review 1975-2005” (eds.) (National Cancer Institute, Bethesda, 2008). The primary cause of death is due to metastasis to distant organs, including bone, liver, lungs, and brain. Although great strides have been made in the treatment of primary tumors in breast cancer, the incidence of fatal metastatic events is still very high. In particular, it is estimated that 10-15% of patients have symptomatic brain metastases (Patanaphan et al., “Breast Cancer: Metastatic Patterns and Their Prognosis,” South Med J 81(9):1109-12 (1988); and Tsukada et al., “Central Nervous System Metastasis From Breast Carcinoma Autopsy Study,” Cancer 52(12):2349-54 (1983)) and in as many as 30% of patients brain metastases are found on autopsy (Cho et al., “Causes of Death and Metastatic Patterns in Patients With Mammary Cancer. Ten-year Autopsy Study,” Am J Clin Pathol 73(2):232-4 (1980); and Lee Y. T., “Breast Carcinoma: Pattern of Metastasis At Autopsy,” J Surg Oncol 23(3):175-80 (1983)). Breast cancer is the second leading cause of CNS metastases (Lee Y. T., “Breast Carcinoma: Pattern of Metastasis At Autopsy,” J Surg Oncol 23(3):175-80 (1983); Kesari et al., “Leptomeningeal Metastases,” Neurol Clin 21(1):25-66 (2003); Nussbaum et al., “Brain Metastases. Histology, Multiplicity, Surgery, and Survival,” Cancer 78(8):1781-8 (1996); and Zimm et al., “Intracerebral Metastases in Solid-Tumor Patients: Natural History and Results of Treatment,” Cancer 48(2):384-94 (1981)), and the clinical prognosis for patients with metastases is poor, with one-year survival rates of 20% (DiStefano et al., “The Natural History of Breast Cancer Patients With Brain Metastases,” Cancer 44(5):1913-8 (1979); and Engel et al., “Determinants and Prognoses of Locoregional and Distant Progression in Breast Cancer,” Int J Radiat Oncol Biol Phys 55(5):1186-95 (2003)).
Treatment includes corticosteroids, radiation therapy, and surgery (Lin et al., “CNS Metastases in Breast Cancer,” J Clin Oncol 22(17):3608-17 (2004)). Recent clinical treatment has focused on developing antagonists for the estrogen receptor, progesterone receptor, and human epidermal growth factor. However, approximately 25% of all patients with breast cancer lack these three receptors and do not respond to standard chemotherapy (Bauer et al., “Descriptive Analysis of Estrogen Receptor (ER)-Negative, Progesterone Receptor (PR)-Negative, and HER2-Negative Invasive Breast Cancer, the So-Called Triple-Negative Phenotype: A Population-Based Study From the California Cancer Registry,” Cancer 109(9):1721-8 (2007); Carey et al., “The Triple Negative Paradox Primary Tumor Chemosensitivity of Breast Cancer Subtypes,” Clin Cancer Res 13(8):2329-34 (2007); Dent et al., “Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence,” Clin Cancer Res 13(15):4429-34 (2007); and Haffty et al., “Locoregional Relapse and Distant Metastasis in Conservatively Managed Triple Negative Early-Stage Breast Cancer,” J Clin Oncol 24(36):5652-7 (2006)). In addition, treatment with trastuzumab, a monoclonal antibody against the human epidermal growth factor-2 receptor, appears to be effective for combating breast cancer in the periphery but not in the central nervous system, and patients treated with trastuzumab show an increased incidence of brain metastases (Bartsch et al., “Trastuzumab Prolongs Overall Survival in Patients With Brain Metastases From Her2 Positive Breast Cancer,” J Neurooncol 85(3):311-7 (2007); and Yau et al., “Incidence, Pattern and Timing of Brain Metastases Among Patients With Advanced Breast Cancer Treated With Trastuzumab,” Acta Oncol 45(2):196-201 (2006)).
Additionally, aggressive tumors often exhibit regions of hypoxia (low oxygen concentration), and hypoxic tumor cells are often resistant to chemotherapy and radiation therapy (Batchelder et al., “Oxygen Dependence of the Cytotoxicity of the Enediyne Anti-Tumour Antibiotic Esperamicin A1,” Br J Cancer Suppl 27:S52-6 (1996); Brizel et al., “Oxygenation of Head and Neck Cancer: Changes During Radiotherapy and Impact on Treatment Outcome,” Radiother Oncol 53(2):113-7 (1999); Comerford et al., “Hypoxia-Inducible Factor-1-Dependent Regulation of the Multidrug Resistance (MDR1) Gene,” Cancer Res 62(12):3387-94 (2002); Nordsmark et al., “Pretreatment Oxygenation Predicts Radiation Response in Advanced Squamous Cell Carcinoma of the Head and Neck,” Radiother Oncol 41(1):31-9 (1996); and Teicher et al., “Classification of Antineoplastic Agents by Their Selective Toxicities Toward Oxygenated and Hypoxic Tumor Cells,” Cancer Res 41(1):73-81 (1981)). Hypoxia-resistant breast cancer tumor cells show increased proliferation, metastasis and poor prognosis (Gruber et al., “Hypoxia-Inducible Factor 1 Alpha in High-Risk Breast Cancer: An Independent Prognostic Parameter?” Breast Cancer Res 6(3):R191-8 (2004); Schindl et al., “Overexpression of Hypoxia-Inducible Factor 1α is Associated With an Unfavorable Prognosis in Lymph Node-Positive Breast Cancer,” Clin Cancer Res 8(6):1831-7 (2002); and Zhong et al., “Overexpression of Hypoxia-Inducible Factor 1α in Common Human Cancers and Their Metastases,” Cancer Res 59(22):5830-5 (1999)). Consequently, inhibition of breast cancer metastasis, including metastasis to the brain, would affect lives of millions of people per year, and in the process would ease a significant economic burden on them, their families, and their caregivers, as well as society as a whole.
Malignant glioblastomas are highly aggressive tumors characterized by rapid proliferation, invasiveness, high vascularization, and resistance to apoptosis and thus most chemotherapy and radiotherapy (Schmitt C. A., “Senescence, apoptosis and Therapy—Cutting the Lifelines of Cancer,” Nat Rev Cancer 3(4): 286-95 (2003). Patients generally survive less than two years from diagnosis (Curran et al., “Recursive Partitioning Analysis of Prognostic Factors in Three Radiation Therapy Oncology Group Malignant Glioma Trials,” J Natl Cancer Inst 85(9): 704-10 (1993); Curran et al., “Survival Comparison of Radiosurgery-Eligible and -Ineligible Malignant Glioma Patients Treated with Hyperfractionated Radiation Therapy and Carmustine: A Report of Radiation Therapy Oncology Group 83-02,” J Clin Oncol 11(5): 857-62 (1993); DeAngelis L. M., “Brain Tumors,” N Engl J Med 344(2): 114-23 (2001)). Current treatment combines radiotherapy with temozolomide chemotherapy, which results in approximately a two year survival rate of 26% (Stupp et al., “Radiotherapy Plus Concomitant and Adjuvant Temozolomide for Glioblastoma,” N Engl J Med 352(10): 987-96 (2005)). Recent research has focused on identifying cellular factors that promote growth and angiogenesis of gliomas in the hopes of identifying new targets for pharmacologic intervention, but none have yet shown specificity or efficacy required for therapeutic use (Wong et al., “Targeting Malignant Glioma Survival Signalling To Improve Clinical Outcomes,” J Clin Neurosci 14(4): 301-8 (2007); and Omuro et al., “What is New in the Treatment of Gliomas?” Curr Opin Neurol 20(6): 704-7 (2007)).
It would be desirable to identify a new target for the treatment of breast cancer malignancies, particularly those that create secondary tumors at sites such as the brain, as well as gliomas. Likewise, identifying compounds that can be used to modulate this target are desirable for the treatment of existing breast cancer tumors and/or gliomas, and the prevention of secondary tumor formation resulting therefrom. Finally, it would be of significant benefit to develop a screening assay that can be used to identify additional compounds that can be used to treat existing breast cancer, gliomas, or secondary tumors resulting therefrom.
The present invention is directed to overcoming these and other deficiencies in the art.